KCNH2

KCNH2 is the gene that encodes the alpha subunit of the hERG potassium channel, a member of the ether-a-go-go (KCNH) family. The hERG channel forms a voltage-gated potassium channel that underlies the rapidly activating delayed rectifier current (IKr) in cardiac myocytes, playing a key role in repolarization of the cardiac action potential and helping to determine the QT interval on the electrocardiogram.

The gene is located on chromosome 7 (7q36.1) and generates multiple transcripts through alternative promoters and splicing, including the hERG1a and hERG1b isoforms. The encoded protein assembles as a tetramer to form a functional channel, and proper trafficking to the cell membrane is essential for normal channel activity. The IKr current has rapid activation and inactivation properties that contribute to the characteristic repolarizing current.

Mutations in KCNH2 are a well-established cause of congenital long QT syndrome type 2 (LQT2). Loss-of-function mutations reduce IKr, prolong the QT interval, and increase the risk of torsades de pointes and sudden cardiac death, particularly in the presence of certain drugs or electrolyte disturbances. Rare gain-of-function mutations have been associated with short QT syndrome and other arrhythmias. The penetrance and clinical presentation of LQT2 are variable.

Pharmacologically, the hERG channel is a common off-target for several medications; unintended IKr blockade can lead to acquired long QT syndrome and arrhythmias. As a result, hERG screening is standard in drug development. Management of LQT2 focuses on avoiding QT-prolonging drugs, using beta-adrenergic therapy, and, in high-risk cases, interventions such as left cardiac sympathetic denervation or an implantable cardioverter-defibrillator.